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Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase

Andersson, Lotta E. LU ; Shcherbina, Liliya LU ; Al-Majdoub, Mahmoud LU ; Vishnu, Neelanjan LU ; Arroyo, Claudia Balderas LU ; Carrara, Jonathan Aste ; Wollheim, Claes B. LU ; Fex, Malin LU ; Mulder, Hindrik LU orcid and Wierup, Nils LU , et al. (2018) In Diabetes 67(3). p.372-384
Abstract

Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and... (More)

Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
67
issue
3
pages
13 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:29229616
  • scopus:85042590210
ISSN
0012-1797
DOI
10.2337/db16-1441
language
English
LU publication?
yes
id
c233f0c4-c320-49b2-97e6-9aefeff27d51
date added to LUP
2018-03-17 18:54:56
date last changed
2024-04-01 02:43:43
@article{c233f0c4-c320-49b2-97e6-9aefeff27d51,
  abstract     = {{<p>Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.</p>}},
  author       = {{Andersson, Lotta E. and Shcherbina, Liliya and Al-Majdoub, Mahmoud and Vishnu, Neelanjan and Arroyo, Claudia Balderas and Carrara, Jonathan Aste and Wollheim, Claes B. and Fex, Malin and Mulder, Hindrik and Wierup, Nils and Spégel, Peter}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{372--384}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase}},
  url          = {{http://dx.doi.org/10.2337/db16-1441}},
  doi          = {{10.2337/db16-1441}},
  volume       = {{67}},
  year         = {{2018}},
}